One of the major challenges of pancreatic ductal adenocarcinoma (PDAC) is the identification, development and validation of novel molecular markers and imaging probes that would enable earlier detection and provide a rational guide for treatment regimens. We are proposing the integrin subtype ?v?6 as a novel molecular imaging marker for further development and validation combined with a non-invasive peptide-based molecular imaging strategy for in vivo detection of disease progression. ?v?6 is an epithelial-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelial derived cancers. This receptor is often localized to the invasive front of tumors and plays a key role in invasion and metastasis. ?v?6 was initially identified in pancreatic cancer with the majority of human PDAC samples tested receiving the maximum score from IHC. The PI has developed an ?v?6-directed molecular imaging agent, 18F-?v?6-binding-peptide (18F-?v?6-BP), which has high affinity and selectivity for ?v?6 integrin and demonstrated favorable pharmacokinetics in tumor-bearing mice and non-human-primates. Approval to proceed with a first-in-human study was recently granted by the FDA. The overall goal of this U01 is to validate ?v?6 integrin as a non-invasive molecular imaging target for the early detection of PDAC with PET using 18F-?v?6-BP. Our three Aims will run in parallel over this five year proposal. In Aim 1 a) we will evaluate ?v?6 expression in human pancreatic tissue (IPMN, MCN and PDAC), and b) we will evaluate ?v?6 expression non-invasively in murine pancreatic cancer progression models of IPMN or MCN to PDAC using small animal PET imaging to determine if ?v?6 is a useful marker to evaluate progression of neoplastic transformation. In Aim 2 we will perform a human prospective cohort study evaluating ?v?6 imaging. Patient with suspect PDAC and cystic pancreatic lesions (IPMN or MCN) will get standard of care (SOC) treatment, molecular analysis of the aspirate and 18F-?v?6-BP-PET/CT. We will compare a) SOC and molecular testing with 18F-?v?6-BP-PET/CT imaging in risk stratification and b) 18F-?v?6-BP-PET/CT imaging with resected specimen pathology. In Aim 3 we will develop a multiplexed targeting strategy to interrogate two molecular markers simultaneously in vivo. We have selected ?v?6 and Plectin-1 as our initial model as both targets have been identified in PDAC and peptide-based targeted molecular imaging agents already exist for each target. This targeted molecular imaging approach facilitates personalized medicine, with ?v?6-directed imaging identifying high-risk precursor lesions for intervention while sparing low risk lesions unnecessary intervention. The team assembled has significant expertise and resources in molecular probe development and small-animal molecular imaging that can be leveraged by the Pancreatic Cancer Detection Consortium for rapid validation of future molecular imaging probes.